The elderly frequently exhibit an altered responsiveness to drugs and the incidence of adverse reactions is significantly higher than in young adults. Investigations are directed toward understanding the factors involved in such changes in man, especially those in the area of drug disposition and pharmacodynamics, so that more rational and safer drug therapy may be utilized. Both specific problems and more general phenomena are to be considered. Multiple drug therapy is common in the elderly and, therefore, drug-drug interactions could be involved in altered clinical responsiveness. Whether interactions at the level of drug metabolism, such as enzyme induction and inhibition are qualitatively or quantitatively similar in the young and the elderly is not known. Studies will be performed to explore this question by examining the time course and extent of induction in these two populations using model interacting drugs. An increase in clinical sensitivity to the commonly prescribed benzodiazepines occurs with aging. The role of altered distribution and/or metabolism of prototype drugs of this class and changes in the disposition of psychopharmacologically active metabolites will be examined in the elderly. This will be coupled with studies designed to quantitatively assess the central depressant activities of the drugs. Accordingly, the relative contributions of altered pharmacokinetics and pharmacodynamics may be determined. Investigation will also be continued to determine any changes which occur with aging in the disposition of the narcotic analgesic, meperidine. Of particular interest are any alterations in absorption following oral and intramuscular administration, and changes in metabolism and distribution.